The goal of this project is to characterize unusual chronic infections with Epstein-Barr virus and to ascertain whether Epstein-Barr virus or other infectious agents can initiate a syndrome of chronic fatigue. We identified and are further exploring a series of clinical and immunologic abnormalities in nearly 140 patients to date. We completed a three year placebo controlled trial of acylovir therapy in 27 patients with the chronic fatigue syndrome and unusual EBV serologic profiles. The trial showed acylovir to be no better than placebo. During the past year we heightened our focus on individuals whose illness began with well defined acute infections particularly documented acute infectious mononucleosis. We further explored the prevalence of antibodies to individual EBNA proteins in both normal and fatigued populations. We have initiated detailed neurologic, neuroendocrologic, and neuropsychologic studies in selected subjects with this syndrome. We also initiated molecular studies of the virus carried by patients with severe chronic Epstein-Barr virus infection and with the chronic fatigue syndrome. To this end we have developed an in-situ hybridization system by which we detect EBV gene expression at increased rates in the tissues of some patients with chronic EBV infections.